Ex vivo manufacture of clinically effective engineered bone requires the incorporation of bioactive factors into a biomaterial scaffold that will stimulate vascular infiltration, tissue integration and remodeling in vivo. Polyurethanes are a class of durable biocompatible polymers well suited for numerous biomedical applications. We hypothesize that we can use known structure-property relationships to synthesize a family of novel high modulus, degradable, biocompatible segmented polyurethanes that are capable of supporting bone tissue formation. Concurrently, bone marrow stromal cells (BMSCs) are a class of adult stem cells that readily form mature bone in vivo and can be directed ex vivo to differentiate and secrete a bone like extracellular matrix. We hypothesize that by culturing BMSCs in porous polyurethane scaffolds using novel perfusion strategies to deliver nutrients and oxygen and activate mechanotransductive pathways, we can direct osteoblastic maturation and synthesis of those bioactive factors necessary to stimulate healing in vivo. The goals of the project are: 1) Synthesize a family of high modulus (10-500 MPa) segmented polyurethanes from biocompatible and biologically-derived precursors. 2) Demonstrate biocompatibility, degradability and processibility of polyurethanes into high modulus (0.1 to 5 MPa) porous foam scaffolds. 3) Develop a bone-like tissue ex vivo and determine the effect of polyurethane scaffold modulus and perfusion regimen on ex vivo bone formation. The high-risk innovations of this project are 1) a family of degradable polyurethanes tuned for bone tissue engineering applications, 2) a methodology to process polyurethanes into high porosity, interconnected pore foams with high compressive modulus, and 3) a strategy of intermittent perfusion culture that enhances ex vivo bone tissue development. The results of this project will be a family of engineered bone tissues to be tested in vivo, and methodologies and strategies to construct the next generation of engineered bone tissue.